The only solution to the HIV epidemic in the developing world is a vaccine that either prevents infection or reduces transmission. Recent data from our laboratory suggest that CD4+ T cell responses along with CD8+ T cell responses against subdominant epitopes can lead to control of replication of SIVmac239. The goal of this proposal, therefore, is twofold. First, we would like to investigate the importance of CD4 help in an HIV vaccine. Second, we want to use innovative new technologies to vaccinate for specific peptides rather than whole proteins. This would eliminate the use of large, commonly seen vectors, thereby circumventing immunodominant responses against vector-derived epitopes. Our new vaccination regimen should induce both CD8+ and CD4+ T cells that efficiently control viral replication. Using newly developed, novel vaccine regimens, we hypothesize that vaccinating macaques with CD4 and subdominant CD8 epitopes will generate immune responses that should control SIV replication. [unreadable] [unreadable] In Specific Aim I of the R21, we will induce CTL specific for subdominant Mamu A*01-restricted SIV epitopes. In Specific Aim II we will engender multiple CD4+ T cell responses against epitopes that are commonly seen in SIV-infected elite controller rhesus macaques. [unreadable] [unreadable] In the R33, we will use the most effective vaccine regimen(s) from the R21 phase to engender CD4+ T cell responses and subdominant CD8+ T cell responses. Animals will be vaccinated with subdominant CD8+ T cell epitopes, CD4+ T cell epitopes, or a mixture of the subdominant CD8+ T cell and CD4+ T cell epitopes. These experiments will allow us to elucidate the role of CD8+ T cell responses against subdominant CD8+ T cell epitopes and CD4 help in an effective HIV vaccine. [unreadable] Project Narrative: Recent vaccine trials have failed to protect individuals from HIV infection or reduce transmission of the virus. Using newly developed vaccine modalities, we now have the tools to circumvent problems characteristically seen in common vaccine vectors as well as address the contribution of individual immune responses against HIV. [unreadable] [unreadable] [unreadable] [unreadable]